In previous research Dorus et al. provided evidence of genetic control of in vitro red blood cell (RBC) uptake of Li and in vivo Li distribution across the RBC membrane (RBC Li/plasma Li ratio concentration) using a monozygotic-dizygotic twin study method. Since in vitro RBC Li concentrations and in vivo RBC Li/plasma Li ratio concentrations are significantly correalted, the in vitro assay provides a method for studying Li distribution without having to administer lithium carbonate to normal subjects. The first puspose of the proposed research is the study of in vitro RBC Li concentrations in normal families. Further documentation of genetic control of Li distribution will be provided by the finding that related individuals are more alike than unrelated individuals. In contrast to the twin study method, family studies will provide the opportunity to draw inferences about the probable number of genes involved in controlling Li distribution and their relative dominance. The distribution of Li across the RBC membrane in manic depressive patients as reflected in the RBC Li/plasma Li ratio concentration has received increasing attention. There is evidence that the ratio concentrations of patients responding to lithium carbonate are higher than those of non-responders and that ratios of patients differ from those of normal controls. With regard to the etiology of manic depressive illness, an important question is whether differences in cell membrane function are an inherent, and possibly genetically controlled, characteristic of manic depressive illness, or whether they are related to the pathological state. The second purpose of the proposed research is to assess in vitro RBC uptake of Li in first degree relatives of bipolar probands and normal controls. If manic depressive illness is genetically transmitted, it is reasonable to assume that first degree relatives, including those with no history of affective illness, have a greater genetic load for manic depressive illness than normal controls. Thus, if RBC Li concentrations of first degree relatives differ significantly from those of normal controls, evidence will be provided that cell membrane function is central to the understanding of the genetic transmission of manic depressive illness.